Pulmonary hypertension (PHtn) is a life-threatening condition that can affect all ages, from neonates to adults. The hallmark of this disorder is increased pulmonary arteriolar vasoconstriction and vessel wall remodeling characterized by intimal hyperplasia, excess smooth muscle cell layers in the media, and deposition of extracellular matrix. Although the survival and quality of life has improved in patients with pulmonary hypertension, there is no cure for this disease. The mainstay of current medical treatment falls into several forms of therapy, including the use of vasodilators, anti-coagulants, anti-platelet agents, anti- inflammatory and vascular-remodeling therapies. Hypoxia is a known primary or secondary stimulus for the development of PHtn and various animal models exposed to hypoxia develop the pulmonary and cardiac manifestations that are characteristic of human disease. We have investigated the therapeutic potential of treating hypoxia-induced PHtn with genetically-engineered bone marrow-derived mesenchymal stem cells (MSC) expressing the cytoprotective gene, heme oxygenase-1 (HO-1). Using a mouse model of hypoxia- induced pulmonary hypertension that we and others have characterized, we had previously reported that transgenic mice with lung-specific overexpression of HO-1 driven by the surfactant protein C (SPC) promoter (SHO1) do not develop PHtn in response to hypoxic exposure. Mice deficient in HO-1 have a maladaptive response to hypoxia and in addition to pulmonary hypertension, they develop right ventricular dilatation and infarction compared to wild type animals. We have generated preliminary data showing that transplantation of MSC over-expressing HO-1 via the jugular vein into the lung could reverse hypoxia-induced PHtn in mice deficient in HO-1. Our overall goal is to understand the mechanisms by which MSC inhibit /reverse the development of pulmonary hypertension in the hypoxic mouse model so that we can develop rational therapies for the treatment of this disease in humans. The specific aims of the proposal are: (1) to investigate whether HO-1 is required for the protective action of MSC on the development of pulmonary hypertension, (2) to investigate the mechanisms of MSC homing and engraftment in the lung, and (3) to investigate the basis of MSC repair mechanisms in the hypoxic lung.